Space Motion Sickness (SMS) is often treated in space with promethazine (PMZ). Anecdotal reports indicate that the common side effects of drowsiness and decrements in cognitive performance that are associated with PMZ administration (50 mg intramuscular) on the ground, are absent or less pronounced in space suggesting that the bioavailability and/or pharmacodynamic behavior of PMZ may be altered during space flight. There are limited flight opportunities available for clinical research in space, the PA-00-088, therefore, solicits ground-based research required to improve, or answer specific questions about in-flight diagnosis, therapy, and post-flight rehabilitation. We propose here, to evaluate noninvasive methods for the evaluation of bioavailability and pharmacodynamics of PMZ. The specific objectives of the proposed research are to, 1. Compare pharmacokinetic/pharmacodynamic variables estimated from saliva and plasma levels of PMZ after administration, 2. Estimate the relative bioavailability of the three dosage forms of PMZ that are often administered for the control of motion sickness symptoms in space, and 3. Establish the dose-response relationship of PMZ. We will estimate the bioavailability of an intramuscular injection (TM), oral tablet and rectal suppository in normal subjects during ambulatory and antiorthostatic bed rest (ABR) conditions using novel stable isotope techniques. Drowsiness, cognitive performance and salivary flow rate will be measured as a function of circulating drug concentrations after administration of three TM doses of PMZ. We will compare and contrast the bioavailability of PMZ during normal and ABR conditions to examine changes in drug absorption and availability during ABR and evaluate whether these changes may be similar to those anticipated in a microgravity environment. Results of this study will validate methods for an approved in-flight investigation with this medication awaiting an opportunity for manifestation. These data will also provide the much-needed information on the dynamics and therapeutic index of PMZ and their implications on crew fatigue and performance in space.